N-(substituted-polyhydrocycloalkano{8 b{9 quinolines carboxamides

ABSTRACT

The compounds of this invention are useful in the treatment of mammals for auricular tachycardia. They are effective, potent anti-arrythmic agents with a wide safety margin between effective doses and toxic doses. For example, one of the compounds of this invention is approximately equipotent to quinidine sulfate, with an equally long or longer duration of action, but is only onehalf as toxic as quinidine sulfate.

United States Patent Diamond [72] Inventor:

[73] Assignee:

Julius Diamond, Lafayette Hill, Pa.

William H. Rorer Inc., Fort Washington, Pa.

[22] Filed: Dec.27, 1968 [21] Appl.No.: 787,613

[52] U.S. Cl. ..260/286 R, 260/268 TR, 260/279 R,

260/287 R, 424/250, 424/257, 424/258 [51] Int. Cl ..C07d 39/00, C07d51/70, C07d 37/02 [58] Field of Search ..260/268 TR, 286

[56] References Cited UNITED STATES PATENTS 1,688,469 10/1928 Miescher..260/287 R 2,798,070 7/1957 Cain ....260/287 R 2,798,873 7/1957Macter... ....260/287 R 1,825,623 9/1931 Miescher .....260/287 3,197,4737/1965 Klosa ..260/287 3,232,945 1/1966 Sigal et a1. ..260/288 1 June13, 1972 3,282,943 11/1966 Landgratz et al. ..260/287 X 3,318,896 5/1967Pribyl ..260/287 OTHER PUBLICATIONS Patniak et al., Jour. Med. Chem.Vol. 9, pp. 183- 9 1966) Al-Tai et al., in Chem. Abstr. Vol. 68 C01.39436a 1968) Al-Tai et al. 1, Bull. Coll. Sci. (Baghdad) Vol. 9, pp. 55-8 (1966) Al-Tai et al. II, Bull. Coll. Sci. (Baghdad) Vol. 6 pp. 99- 103(1961) Primary Examiner-Donald G. Daus Attamey-Charles E. Baxley, FrankM. Nolan, Thomas E. Tate and Erich M. H. Radde [5 7] ABSTRACT Thecompounds of this invention are useful in the treatment of mammals forauricular tachycardia. They are effective, potent anti-arrythmic agentswith a wide safety margin between effective doses and toxic doses. Forexample, one of the compounds of this invention is approximatelyequipotent to quinidine sulfate, with an equally long or longer durationof action, but is only one-half as toxic as quinidine sulfate.

4 Claims, No Drawings N-(SUBSTITUTED-POLYHYDROCYCLOALKANO[B ]QUINOLINESCARBOXAMIDES This invention relates to cycloalkano quinolines and thetreatment of mammals with such cycloalkano quinolines as anti-arrythmicdrugs.

The cycloalkano quinolines of this invention have the following formula:

1 coNmoH bNmRmHA in which a is O, l or 2; b is 2 or 3; X is hydrogen,halogen or lower alkoxy; HA is a non-toxic acid; it is O, l or 2; and Rand R are hydrogen, lower alkyl or combined with the N to which they areconnected to be a part of a saturated heterocyclic ring.

The methylene group [Cl-1 may be straight or branched chain, such asmethylene, ethylene or ethylidene. The halogen may be fluorine,chlorine, bromine or iodine. The lower alkoxy and lower alkyl each haspreferably less than five carbon atoms, such as methyl, ethyl, propyl orisobutyl. The acid addi tion salts (HA) may be any non-toxic acid suchas hydrochloric acid, sulfuric acid, citric acid or succinic acid.Examples of the saturated heterocyclic ring are piperidyl or pyrrolidyl.

The compounds of this invention are produced in accordance with thefollowing reaction scheme:

( CO OH lSOClz (5) C ONI'HCIIQ NRJi-THHA In the first step, apolyhydrocycloalkano[b] quinoline carboxylic acid, formula (2) above, isreacted with an excess of thionyl chloride in an inert solvent, such aschloroform by heating with agitation at reflux temperature for about 6hours. The excess thionyl chloride and solvent are removed by vacuumdistillation and the residue triturated with an inert solvent such asbenzene and collected on a filter. The solid is triturated with hotsolvent such as hot benzene to obtain a crude product. Recrystallizationfrom a suitable inert solvent such as a mixture of chloroform andbenzene results in the, corresponding acid chloride hydrochloride,formula (3) above.

In the subsequent steps of the process of producing thev compounds ofthis invention, a suspension of an acid additioni salt of apolyhydrocycloalkano[b] quinoline carbonyl chloride is added dropwise toa solution in an inert solvent, such as toluene, of an amine having theformula:

z 2]b NR1R2 During the addition, the reaction mixture is agitated atreflux temperature. After heating for a period of 4 to 12 hours, themixture is cooled and washed several times with an aqueous solution ofan alkali metal hydroxide such as sodium hydroxide and subsequentlywashed several times with water. The solid is filtered off. The inertsolvent phase is dried over anhydrous potassium carbonate. filtered, andthe inert solvent distilled off under vacuum. The resulting residue maybe purified by any convenient means such as trituration with an inertsolvent or dissolving in an inert solvent and declorization withcharcoal. The resulting product, formula (4) above, may be treated withan anhydrous non-toxic acid such as anhydrous hydrogen chloride gas toproduce the acid addition salt, formula (5) above, and purified by anysuitable means such as precipitation with ether followed by triturationwith an inert solvent such as ethyl acetate.

A more comprehensive understanding of this invention is obtained byreference to the following examples.

EXAMPLE I N-( Z-DIETHYLAMINOETHYL)-6,7,8,9, 10,1 l-HEX- AHYDROCYCLOOCTA(B) QUINOLlNE-lZ-CARBOXA- MIDE Dll-lYDROCHLORlDE Stage 1 Preparation of6,7,8,9,10,l l-hexahydrocycloocta (b) quinoline-12-carbonyl chloride.

43 G (0.169 mole) of 6,7,8,9,l0,l l-hexahydrocycloocta(b)-quinoline-l2-carboxylic acid and 47.6 g (0.4 mole) of thionylchloride in 75 cc of chloroform are heated with stirring at refluxtemperature for 6 hours. The excess thionyl chloride and chloroform areremoved by vacuum distillation, the amber-brown residue triturated with300 cc of benzene, and collected on a filter. The solid is trituratedwith 250 cc of hot benzene and filtered to give a tan solid, 37 g, m.p.209-212 dec. Recrystallization from chloroform-benzene gives the nearlywhite acid chloride hydrochloride, 27 g, m.p. 21 ll2 dec.

Analysis: Calculated for C, H, Cl- NO: C=61.95, H=5.52,

N=4.52, Cl=22.86

Found: C=62, 19, l-l==5.41, N--4.36, Cl=22.76

Stage 2 Preparation of N-(2-diethylaminoethyl)- 6,7,8,9,l0,ll-hexahydrocycloocta (b) quinoline-lZ-carboxamide dihydrochloride.

A suspension of 10 g of 6,7,8,9,l0,l l-hexahydrocycloocta (b) quinolinel2-carbonyl chloride hydrochloride in 200 cc of toluene is added dropwiseduring 1 hour to a solution of 20 g of N,N-diethylethylenediamine in 25cc of toluene while stirring at reflux temperature. After heating for 8hours, the mixture is cooled, washed with 3 X cc of 10% sodiumhydroxide, followed by 3 X 200 cc water, and 5.0 g of solid (A) filteredoff. The toluene phase is dried over anhydrous K CO filtered, and thetoluene distilled off under vacuum to leave a gummy residue whichsolidifies after trituration with ethyl acetate, yield 4.5 g. The latteris taken up in 50 cc isopropanol, decolorized with charcoal andfiltered. After treating with anhydrous hydrogen chloride gas, thesolution is added slowly to 700 cc of ether to precipitate thedihydrochloride which is triturated with ethyl acetate, yield 4.5 g (B).The two solids (A and B) are combined in 25 cc of methanol, and themethanol is displaced with acetone to precipitate the dihydrochloride,9.0 g, m.p. 2425 dec. Recrystallization from methanol-acetone gives 8 gwhite dihydrochloride 243-5.

Analysis: Calculated for C H Cl N O: C=61.97, H=7.80,

N=9.85 Found: C=61.9l, H=7.82, Ni.

EXAMPLE II N-(3-DIISOPROPYLAMINOPROPYL)-6,7,8,9,10,1 l-HEX-AHYDROCYCLOOCT A B)-QUlNOLlNE- l Z-CARBOXA- MlDE DIHYDROCHLORIDE Theprocedure in Example I is followed except that N,N-diisopropyl-l,3-propylenediamine is substituted for N,N-diethylethylenediamine.

EXAMPLE III N-PlPERlDlNOETl-lYL-6,7,8,9, 10, l l-HEXAl-IYDRO- CYCLOOCTA(B) QUlNOLINE-lZ-CARBOXAMIDE DIHYDROCHLORIDE The procedure in Example Iis followed except that 2- piperidinoethylamine is substituted for N,N-diethylethylenediamine.

EXAMPLE IV N-(PlPERAZlNOETHYL)-6,7,8,9,10,l l-HEXAHYDRO- CYCLOOCTA (B)QUINOLINE-lZ-CARBOXAMIDE DIHYDROCHLORIDE The procedure in Example I isfollowed except that 2- piperazinoethylamine is substituted for N,N-diethylethylenediamine.

EXAMPLE V N-( 2-DIETHYLAMINOETHYL )-7 ,8,9, lO-TETRAHYDRO- GH-CYCLOHEPTA[B] QUINOLINE-l l-CARBOXAMIDE DIHYDROCHLORIDE The procedure in Example Iis followed except that the starting material is7,8,9,lO-tetrahydro-6H-cyclohepta[b] quinoline-l l-carboxylic acid.

EXAMPLE VI N-(Z-DIETHYLAMINOETI-lYL)-6,7,8,9-TETRAHYDRO- CYCLOHEXA( B)QUINOLINE- 1 O-CARBOXAMIDE DIHYDROCHLORIDE The procedure in Example I isfollowed except that the starting material is6,7,8,9-cyclohexa[b]quinoline-lO-carboxylic acid.

EXAMPLE VII 2-CHLORO-N-(2-DIETHYLAMINOETHYL)-6,7,8,9,10,1l-HEXAHYDROCYCLOOCTA BQUINOLINE- l Z-CAR- BOXAMIDE DIHYDROCHLORIDE Theprocedure in Example I is followed except that the starting material is2chloro-6,7,8,9,l0,l l-hexahydrocycloocta[b]quinoline-1Z-carboxylicacid.

EXAMPLE VIII 2-METHOXY-N-( Z-DIETHYLAMINOETHYL 6,7,8,9,l0,ll-HEXAHYDROCYCLOOCTA{B]QUIN- OLINE- l Z-CARBOXAMIDE DIHYDROCHLORIDE Theprocedure in Example I is followed except that the starting material is2-methoxy-6,7,8,9,10,l l-hexahydrocycloocta[ b]quinolinel 2-carboxylicacid.

The carboxamides and acid addition salts of this invention are effectivein treating tachycardia and arrythmias when administered to mammals.Their efficacy is illustrated by the reversal of aconitine-inducedtachycardia and the reversal of ouabain-induced arrythmias in mammalseffected by the administration of .N-( 2-diethylaminoethyl)-6,7,8,9,l0,1l-hexahydrocycloocta (b) quinolinel 2-carboxamide dihydrochloride.

Aconitine-induced tachycardia is produced by the initial administrationof aconitine to a mammal. Aconitine is an alkaloid which is a peripheraland central stimulant. When applied directly to cardiac tissue in thearea of the SA node, it increases the excitability and results in anauricular tachycardia of long duration. Antiarrythmic drugs such asquinidine sulfate and procainamide can block the auricular tachycardiainduced by aconitine due to an increase in refractory period.

As a test system, the anesthetized dog is maintained under positivepressure breathing, and the heart is exposed with open chest surgery. Asmall cotton pellet saturated with 0.05% aconitine is inserted in theright atrium in the area of the SA node with an immediate response ofauricular tachycardis. The test compound is then given and the percentdecrease in actual tachycardia is recorded as the positive end point.

Arrythmias is effected by the administration of ouabain to a mammal.Ouabain is a cardiac glycoside which at larger dosages is capable ofproducing arrythmias similar to many forms of pathological arrythmias.Ouabain increases vagus tone giving rise to a decreased atrial rate. Atthe same time it reduces the ventricular refractory period which permitsthe generation of ectopic beats and ultimately a ventriculartachycardia. The situation is generally characterized by a reversal indirection of the QRS complex. Anesthetized dogs are given ouabain at 70meg/kg, i.v. ECG (Standard Lead II) is monitored and if no ventriculartachycardia occurs in 30 minutes, a booster injection of 20 meg/kg isgiven. The test compound is then given and the ECG pattern and heartrate are recorded. Antiarrythmic drugs produce a reversion of the ECGpattern and a decrease in heart rate.

N-(Z-diethylaminoethyl)-6,7,8,9,10,1 l-hexahydrocycloocta[blquinoline-l2-carboxamide dihydrochloride manifested activity inreversing aconitine induced tachycardia when given intravenously. Theaverage effective dose of the tested compound in 3 dogs was 7.0 mg/kgwhich places that compound in the same potency range as quinidinesulfate (average effective dose is 6.6 mg/ kg, i.v.). When givenintraduodenally the tested compound was active at doses between 20 and40 mg/kg in reversing aconitine-induced tachycardia. The onset time wasdelayed somewhat, but the length of activity was prolonged (greater than4 hours). Quinidine sulfate under the same conditions was effective atdoses between 30 and 40 mg/kg, duration of action greater than 3 hours.The tested compound reversed ouabain-induced arrythmia in dogs at a doseof 5 mg/kg. (i.v. The length ofactivity was greater than 2 hours.

The carboxamides and their acid addition salts are nontoxic in dosagesemployed in the treatment of tachycardia in mammals, as shown bytoxicity tests with N-(2-diethylaminoethyl )-6,7,8,9, l0, 1l-hexahydrocycloocta( b)quin0linel 2-carboxamide dihydrochloride.

In this testing male Swiss albino mice was randomly separated intogroups of 10. The test compound was given orally as a water suspensioncontaining 2 drops of Tween per 10 ml. The animals were observed formortality over a 5 day period. The LD of the tested compound wascalculated to be 1,280 mg/kg. (p.o. The LD of quinidine sulfate is 593mg/kg. (p.o.).

The testing of N-(Z-diethylaminoethyl)-6,7,8,9,l0,ll-hexahydrocycloocta( b )quinolinel 2-carboxamide dihydrochloride indogs indicates that it is an orally effective potent antiarrythmic agentwith a wide safety margin between effective doses and toxic doses. Thecompound is approximately equipotent to quinidine sulfate, with anequally long or longer duration of action, but is only one-half as toxicas quinidine sulfate. The data indicates that the therapeutic ratio ofthe tested compound is substantially more favorable than quinidinesulfate, which would meet one of the main objectives of research in theantiarrythmic field.

What is claimed is:

l. A compound having the formula:

in which a is O, l or 2; b is 2 or 3; X is hydrogen, halogen or loweralkoxy having less than five carbon atoms; HA is a non toxic acid; n is0, /z, I or 2, R, and R are hydrogen, lower alkyl having less than fivecarbon atoms or combined with the N to which they are connected to bepart of a saturated heterocyclic ring selected from the group consistingof piperidino, pyrrolidino and piperazino.

2. A compound of claim 1 in which n is 0.

3. A compound of claim 1 in which the lower alkoxy group has less thanfive carbon atoms.

4. A compound of claim 1 which is diethylaminoethyl )-6,7 ,8 ,9, l 0,1 l-hexahydrocycloocta[ b]quinoline-l 2-carboxamide dihydrochloride.

at a: 0: t

2. A compound of claim 1 in which n is
 0. 3. A compound of claim 1 in which the lower alkoxy group has less than five carbon atoms.
 4. A compound of claim 1 which is N-(2-diethylaminoethyl)-6,7,8, 9,10,11-hexahydrocycloocta(b)quinoline-12-carboxamide dihydrochloride. 